Mueller Rudolf, Reddy Virsinha, Nchinda Aloysius T, Mebrahtu Fanuel, Taylor Dale, Lawrence Nina, Tanner Lloyd, Barnabe Marine, Eyermann Charles J, Zou Bin, Kondreddi Ravinder R, Lakshminarayana Suresh B, Rottmann Matthias, Street Leslie J, Chibale Kelly
Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
Drug Discovery and Development Centre (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South Africa.
ACS Omega. 2020 Mar 17;5(12):6967-6982. doi: 10.1021/acsomega.0c00327. eCollection 2020 Mar 31.
A phenotypic whole cell high-throughput screen against the asexual blood and liver stages of the malaria parasite identified a benzimidazole chemical series. Among the hits were the antiemetic benzimidazole drug Lerisetron (IC NF54 = 0.81 μM) and its methyl-substituted analogue (IC NF54 = 0.098 μM). A medicinal chemistry hit to lead effort led to the identification of chloro-substituted analogue with high potency against the drug-sensitive NF54 (IC NF54 = 0.062 μM) and multidrug-resistant K1 (IC K1 = 0.054 μM) strains of the human malaria parasite . Compounds and gratifyingly showed in vivo efficacy in both and mouse models of malaria. Cardiotoxicity risk as expressed in strong inhibition of the human ether-a-go-go-related gene (hERG) potassium channel was identified as a major liability to address. This led to the synthesis and biological assessment of around 60 analogues from which several compounds with improved antiplasmodial potency, relative to the lead compound , were identified.
针对疟原虫无性血液期和肝脏期进行的全细胞表型高通量筛选，确定了一个苯并咪唑化学系列。筛选出的活性化合物包括抗呕吐苯并咪唑药物来立司琼（对NF54株的半数抑制浓度ICNF54 = 0.81 μM）及其甲基取代类似物（ICNF54 = 0.098 μM）。通过从活性化合物到先导化合物的药物化学研究，确定了一种氯取代类似物，它对药物敏感的NF54株（ICNF54 = 0.062 μM）和多药耐药的K1株（ICK1 = 0.054 μM）的人类疟原虫具有高效力。令人欣慰的是，化合物 和 在疟原虫感染的 和 小鼠模型中均显示出体内疗效。对人类醚 - 去极化相关基因（hERG）钾通道的强烈抑制所表现出的心脏毒性风险，被确定为需要解决的主要问题。这促使合成并对约60种类似物进行生物学评估，从中鉴定出了几种相对于先导化合物 抗疟效力有所提高的化合物。
